Sucrose is generally regarded as the major cause of dental caries in western countries, because of its ubiquity in the diet. There are currently only three substances approved for use in the United States as high-intensity (non-nutritive) sweeteners, namely, saccharin and aspartame, and acesulfame K, which are used in place of sucrose in foods, beverages, and medicines. However, because questions have been raised in both the scientific literature and the popular press about the safety or sweetness quality of these substances, there is an intensive search being conducted to discover new noncariogenic and noncaloric sucrose substitutes. The plant kingdom has already afforded a number of intense sweeteners of commercial significance, such as thaumatin, stevioside, and glycyrrhizin. The objective of this investigation, therefore, is to isolate novel potentially noncariogenic natural intense sweetening agents from several plant species already identified as being sweet, as well as from other sweet plants that will be procured during the project on the basis of literature reports and observations in the field. Plant extracts and chromatographic fractions will be monitored for sweetness using previously established gerbil electrophysiological and behavioral bioassays. Pure isolates suspected as being sweet as a result of observations in the gerbil will be tested for mutagenicity and for acute toxicity in mice. Compounds deemed nonmutagenic and nontoxic will then be assessed for sweetness by a small number of human volunteers. The structures of sweet isolates will be determined by spectroscopic and chemical methods. It is hoped that at least one new sweetener to be obtained in this project may ultimately have use as a safe noncariogenic and non-nutritive sweetening agent. Alternatively, certain compounds may serve as prototype molecules for the synthesis of sweeter or more pleasant-tasting analogues. The discovery of novel sweet compounds of natural origin should also increase existing knowledge on structure-sweetness relationships, and be of use in investigations designed to rationally design sweet molecules.